At any given time, a large segment of the U.S. population is on a "serious" diet to lose weight for either medical or psychological/cosmetic reasons. As judged by the number of "recommended" diets, dieting publications, exercise regimens, and weight loss preparations, there is no universally acceptable method to reduce weight. Weight control has therefore evolved into a very large industry in the United States with consumer spending of about $10 billion annually. J. Rosenblatt and S. Stencel, "Weight Control--A National Obsession," 1982 Congressional Quarterly, Vol. II, No. 19, 855 et seq. Currently, the prevalent social view of obesity is conditioned by cosmetic considerations which shifts to medical considerations only when weight gain becomes extreme. Rosenblatt and Stencel, page 4, supra; "Slimming Food," Mintel Publications, December 1982.
Severe dieting can also lead to extreme weight loss, possibly inducing the condition known as anorexia nervosa in which many victims starve themselves to death. Existing pharmacological means for weight loss and weight control, such as amphetamines, are powerful habit-forming drugs with dangerous side effects, and other drugs for this purpose are either ineffective or dangerous. Rosenblatt and Stencel, supra. There is a need for safe and efficacious compositions and methods to control weight.
U.S. Pat. No. 4,217,353 issued to Smith on Aug. 12, 1980, discloses that the narcotic antagonist, naltrexone ((-)-17-cyclopropylmethyl-4,5.alpha.-epoxy-3,14-dihydroxymorphinan-6-one), can be administered orally to effect appetite suppression in mammals. Holtzman, J. Pharmacol. Exp. Ther., 189, 51-60 (1974), has shown that the narcotic antagonist naloxone (N-allyl-14-hydroxy-7,8-dihydronormorphinone) suppresses eating by food-deprived rats but not by food-deprived mice. In a subsequent study, Holtzman showed that the fluid intake (sweetened Enfamil.TM. baby formula) of rats was reduced following subcutaneous administration of naloxone, naltrexone or nalorphine (N-allylnormorphine); Life Sciences, 16, 1465-70 (1975).
Japanese Pat. No. 1442 (1964) to Sankyo describes an analgesic compound of the formula: ##STR1##
Japanese Pat. No. 6683 (1964) to Sankyo describes an analgesic compound of the formula: ##STR2##
The N-methyl compound: ##STR3## is also listed in CAS-OnLine.TM. as "references not available"; the corresponding O-methyl compound is mentioned in Bognar et al., Collect. Czech. Chem. Commun., 40 (3), 670-680 (1975), where it was studied as part of an investigation of circular dichroism.
Japanese Pat. No. 1443 (1964) to Sankyo describes narcotic antagonists of the formula: ##STR4## where R=H or Me and R.sub.1 =allyl or propargyl.
Japanese Pat. No. 3625 (1966) to Sankyo describes antipyretic and antitussive compounds of the formula: ##STR5## where R=lower alkyl or aralkyl; and Y is H, oxo, OH, etc.
Japanese Pat. No. 3702 (1966) to Sankyo describes analgesic and antitussive compounds of the formula: ##STR6## where R is lower alkyl; and Y=ketone, .alpha.- or .beta.-OH, H, or ethylenedioxy.
Japanese Pat. No. 40-22189 (1965) to Sankyo claims an O-demethylation reaction producing ##STR7## where Y=oxo, .alpha.- or .beta.-OH, or H. Where Y=H, the 17-phenethyl compound and its HCl salt are specifically described.
Olofson et al., U.S. Pat. No. 4,141,897, describes compounds related to those of the subject case as substrates for an N-dealkylation method. All bear protecting groups on the 3- and 14-hydroxy groups. (Claim 1) Corresponding N-acylated or N-nor compounds are described in Olofson et al., U.S. Pat. No. 4,161,597.
A pending application, U.S. Ser. No. 437,324, filed Oct. 28, 1982, claims use of nalbuphine (17-cyclobutylmethyl-4,5.alpha.-epoxymorphinan-3,6.alpha.,14-triol) and nalmefene (former USAN, nalmetrene; 17-cyclopropylmethyl-4,5.alpha.-epoxy-6-methylenemorphinan-3,14-diol) as anorectics.
Such hydroxy opiate derivatives as those described above possess a diverse spectrum of activities, and there is no indication in the known art that the 17-cycloalkylmethyl-4,5.alpha.-epoxy-morphinan-3,14-diols of this invention would be effective appetite suppressants.
The Chemical Abstracts Service CAS-OnLine.TM. computer file does however, contain a record containing the following structures
______________________________________ R Reg. No. ______________________________________ ##STR8## ##STR9## 75768-72-875752-05-5 ______________________________________
No information whatsoever, however, is listed with regard to the synthesis or possible utility of the compounds. The computer record merely notes "references not available."